We report the characterization of a member of the DNA excision repair gene family that is enhanced in cells expressing high levels of insulin receptors or various growth factor receptor tyrosine kinases. The partial hamster ERCC-1 cDNA was cloned by reverse-transcription polymerase-chain reaction of total cellular RNA extracted from Chinese hamster ovary cell lines expressing human insulin receptors (CHO/HIRc). It encodes a protein whose overall homology at the amino acid level is 91.3% and 96% with human and murine ERCC-1, respectively. CHO/HIRc cells and cells overexpressing functionally active IGF-1 receptors and EGF receptors induced an increase of mRNA levels for ERCC-1 gene versus control CHO/neo cells. The enhanced expression of ERCC-1 mRNA in CHO/HIRc cells compared to control CHO/neo cells cannot be ascribed to cell cycle-dependent expression of the ERCC-1 gene. Moreover, this activation of ERCC-1 gene was absent in cells expressing kinase-deficient insulin receptors or a mutant form of the receptor with a substitution of tyrosine for phenylalanine at position 960 in the juxtamembrane region of the protein. There was a correlation between the level of ERCC-1 gene expression and cell survival after UV irradiation. Finally, the enhanced ERCC-1 gene expression was independent of glucose utilization since the rate of glucose consumption was identical in all cell lines. Taken together, these data support an association between receptor tyrosine kinase activity and enhancement of ERCC-1 expression and function.